A Halogen-Atom Transfer (XAT)-Based Approach to Indole Synthesis Using Aryl Diazonium Salts and Alkyl Iodides

Indoles are among the most important N-heterocycles in pharmaceuticals. Here, we present an alternative to the classic Fischer indole synthesis based on the radical coupling between aryl diazoniums and alkyl iodides. This iron-mediated strategy features a double role for the aryl diazoniums that sequentially activate the alkyl iodides through halogen-atom transfer and then serve as radical acceptors. The process operates under mild conditions and enables the preparation of densely functionalized indoles.


General Experimental Details
All required fine chemicals were used directly without purification unless stated otherwise. All air and moisture sensitive reactions were carried out under nitrogen atmosphere using standard Schlenk manifold techniques. All solvents were bought from Acros as 99.8% purity. 1 H and 13 C Nuclear Magnetic Resonance (NMR) spectra were acquired at various field strengths as indicated and were referenced to CHCl3 (7.26 and 77.0 ppm for 1 H and 13 C respectively). 1

General procedure for the preparation of alkyl iodides (Appel reaction) -GP1
To a stirred solution of the alcohol (1.0 equiv.) in CH2Cl2 (0.1 M) were added PPh3 (1.2 equiv.), imidazole (1.2 equiv.) and I2 (1.2 equiv.) under N2 atmosphere at 0 °C. The reaction was stirred for 16 h at room temperature and then diluted with H2O (30 mL). The mixture was extracted with CH2Cl2 (30 mL ×3). The combined organic layers were washed with Na2S2O3 sat., (30 mL), brine (30 mL), dried over MgSO4, filtered and evaporated. Purification by flash column chromatography eluting petrol-EtOAc on silica gel gave the products. Data in accordance with the literature. 8
All diazonium salts were used directly after filtration following recrystallisation. If necessary, the product was dried under a stream of N2 gas but never under reduced pressure or by heating (see safety note below).
Safety note: Diazonium salts are inherently unstable molecules and decompose to release a molar equivalent of N2 gas. While no incident has been observed in our laboratory, diazonium salts must be handled with great care. All diazonium salts were dried under atmospheric pressure at room temperature, under a flow of air or nitrogen, were manipulated with PTFE spatula, never exposed to metal surfaces, and stored in the freezer. We synthesized diazonium tetrafluoroborate salts to mitigate the explosion risk.
Note: Distilling aniline before use is recommended to increase the shelf-life and stability of the corresponding diazonium salts.

4-Methoxybenzenediazonium Tetrafluoroborate (1)
Following GP2a, p-anisidine (2.46 g, 20.0 mmol) gave 4-methoxybenzenediazonium tetrafluoroborate 1 as a solid (4.28 g, 97%). 1    In spite of the excellent NMR yields obtained (Table S1), this methodology suffered from difficult separation, probably because of the organic by-products arising from a Gomberg-S13 Bachmann mechanism and/or from a HAT/XAT sequence involving the amine. We therefore turned our attention towards the use of other reductants.

Reaction Optimization with Different Reductants
General Procedure for the Reaction Optimization with Different Reductants (Diazene

Formation) -GP4
A dry tube equipped with a stirring bar was charged with tert-butyl 4-iodopiperidine-1-  All the reductants screened gave the desired product (Table S2), with the exception of rongalite.
Among them, NaBH(OAc)3 (Table S2, entry 10) and FeSO4•7H2O (Table S2, entry 11) were the most efficient ones. A screening of different Fe(II) salts proved FeSO4•7H2O to be the best candidate (not shown here). We decided to carry out the solvent screening with those two reductants (Table S3). During the optimization, it was noted that the granulometry of Fe(SO4)•7H2O had an impact on the outcome of the reaction: finely ground Fe(SO4)•7H2O resulted in violent gas evolution and consistently lower yields than commercial samples. On the other hand, selecting only larger particle-sized Fe(SO4)•7H2O give a slower reaction but slightly higher yields. However, for convenience, commercial samples containing particles of different sizes were used. S16

Iodides -GP6
Step i: A dry tube equipped with a stirring bar was charged with tert-butyl 4-iodopiperidine-1- Step ii: The crude material was redissolved in CHCl3 (1 mL, 0.1 M) followed by addition of the acid. The reaction was stirred at the given temperature for 16 hours (if heating was required, the reaction vessels were placed in an oil bath). NH4Cl sat. (3 mL) and CHCl3 (3 mL) were added and the mixture was shaken vigorously. 1,3-Dinitrobenzene (17 mg, 0.1 mmol, 1.0 equiv.) was added and the layers were separated. The aqueous layer was extracted with CHCl3, the combined organic layers were dried (MgSO4), filtered and evaporated. CDCl3 (0.5 mL) was then added and the mixture was analysed by 1 H NMR spectroscopy.
As the results in Table S5 show, reaction with 2 equivalents of trifluoroacetic acid (TFA) at room temperature resulted in a 1 H NMR yield of 67% for indole 40 over two steps and marked the endpoint of the optimization (Table S5, entry 11).

Procedure for 1 mmol scale reaction
Step i:  Step ii: The crude mixture from step i was placed under N2 atmosphere in a round-bottom flask capped with a septum. Anhydrous and degassed CHCl3 (5 mL) was added (a red solution is observed) and the contents of the flask were transferred via syringe to an oven-dried 35 mL microwave vial equipped with a stirring bar under N2 atmosphere. This was repeated two times S31 (2.5 mL x 2) before addition of TFA (151 mL, 2.0 mmol, 2.0 equiv.) upon which the solution immediately darkens. The vial was sealed with parafilm, placed in a pre-heated oil bath, and stirred overnight at 55 °C. The crude mixture was evaporated under reduced pressure, redissolved in CH2Cl2 (10 mL) and washed with NaHCO3 sat. (10 mL). The aqueous layer was extracted with CH2Cl2 (20 mL x 3), dried over MgSO4, filtered, and evaporated. The crude mixture was purified by column chromatography on silica gel eluting petrol-EtOAc (7:3) to give 43 as a solid (235 mg, 67%).

HRMS Detection of Fe(III)
The aqueous layer after NH4Cl sat. work-up of the first step (formation of the diazene 3) was submitted to HRMS.

Prussian Blue Test
In order to support the formation of Fe (